Project Summary/Abstract The incidence of type 2 diabetes mellitus is reaching epidemic proportions, becoming one of the major causes of morbidity and mortality across the globe. Despite periods of feeding and fasting, plasma glucose in normal individuals remains in a narow range. Several studies have demonstrated that defects in the stimulation of non-oxidative glucose metabolism by insulin may be among the primary lesions in insulin resistance. In skeletal and cardiac muscle, insulin stimulates glycogen accumulation through a coordinate increase in glucose transport and regulation of glycogen metabolizing enzymes, while in liver insulin blocks glucose output by inhibiting gluconeogenesis, promoting glycogenesis and blocking glycogenolysis. We have made the important discovery of a novel signaling pathway involving ubquitination in the regulation of glycogen metabolism. Our studies demonstrate that during glycogenolysis, several enzymes involved in its metabolism translocate to the nucleus and interact with the E3 ubiquitin ligase Malin for subsequent proteasomal degradation. Additional studies indicate that the dual specificity phosphatase Laforin acts as a molecular scaffold for this process. A fundamental unanswered question is: how hormones such as insulin and glucagon regulate the cellular function of these proteins, and how these novel pathways are dysregulated in metabolic diseases such as diabetes and obesity. This proposal will address these questions by examining the hypothesis that hormones such as insulin and glucagon regulate the formation of protein complexes involved in the degradation of glycogen-associated proteins. We have identified STBD1 as a novel Laforin interacting protein (STBD1) that enhances glycogen synthesis and interacts with several other glycogen associated proteins. Our model suggests that STBD1 is critical for the assembly of complexes targeted for Malin mediated degradation. We will test our model and reveal the mechanisms behind these events by using a combination of biochemical, cellular and transgenic techniques to address three specific aims: (1) to assess how liver specific STBD1 expression in mice affects whole body glucose homeostasis in normal and diabetogenic states; (2) to investigate the role of STBD1 in regulating the proteasomal degradation of glycogen associated proteins by Malin; and (3) to determine the hormonal and cellular signals that regulate STBD1 function. Accomplishing these aims will provide new insight into how hormones control glycogen metabolism, and how this process is dysregulated in metabolic disorders such as diabetes and obesity. Importantly, this can ultimately identify novel therapeutic avenues in these diseases. '